– Patisiran Achieves Mean 7.0 Point Decrease in
Modified Neuropathy Impairment Score (mNIS+7), Comparing Favorably
with Expected Mean 26-30 Point Increase Estimated from Historical
Data –
– In New Post-Hoc Analysis, Evidence for
Potential Halting or Improvement of Neuropathy Progression Seen
Across Broad Range of Baseline Neuropathy Severity –
– In Addition, Company Reports First-Ever
Histological Evidence for Decrease in Dermal TTR Amyloid Burden
Associated with Patisiran Administration –
Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi
therapeutics company, announced today final 24-month results from
its Phase 2 open-label extension (OLE) study of patisiran, an
investigational RNAi therapeutic targeting transthyretin (TTR) for
the treatment of hATTR amyloidosis. These clinical data are being
presented at the American Academy of Neurology (AAN) 2017 Annual
Meeting, held April 22 – 28, 2017 in Boston, Massachusetts. New
results (N=26) showed a mean decrease in the modified neuropathy
impairment score (mNIS+7) at 24 months that provides continued
evidence that patisiran has the potential to halt or improve
neuropathy progression in patients with hATTR amyloidosis. In a new
post-hoc analysis, patisiran showed a mean improvement in mNIS+7
across the full range of neuropathy severity at baseline. Moreover,
patisiran administration was found to be associated with
statistically significant decreases in TTR amyloid deposition as
measured from a blinded analysis of skin biopsy samples. Finally,
patisiran was found to be generally well tolerated, with no
drug-related serious adverse events (SAEs) for up to 25 months of
treatment or drug-related discontinuations. Dosing continues for
all eligible Phase 2 OLE patients (N=25) who have now transitioned
into the ongoing APOLLO-OLE study. The Company remains on track to
present top-line results from its ongoing APOLLO Phase 3 study of
patisiran in mid-2017.
“We are encouraged to see the final 24-month results from our
Phase 2 OLE which provide continued evidence suggesting that
patisiran can potentially halt or improve neuropathy progression in
patients with hATTR amyloidosis. We are also pleased to present the
first-ever clinical evidence that patisiran administration is
associated with a decrease in dermal TTR amyloid burden, which we
believe further supports the therapeutic hypothesis that TTR
knockdown can potentially lead to reduction of amyloid deposits in
the body,” said Eric Green, Vice President, General Manager, TTR
Program. “All eligible Phase 2 OLE patients have now rolled over to
the ongoing, global APOLLO-OLE trial, and we plan to present
36-month data from this cohort of patients in late 2017.”
Final 24-month results from the Phase 2 OLE study showed a mean
decrease in mNIS+7 of 7.0 points after 24 months of patisiran
administration. This compares favorably to an expected mean
increase in mNIS+7 of 26 to 30 points at 24 months estimated from
an analysis of historical data sets in untreated hATTR amyloidosis
patients with similar baseline characteristics (Adams et al.,
Neurology, 2015;85:675-682; Berk et al.,
JAMA, 2013;310:2658-67). In an analysis of individual
responses, 74 percent of patients showed either an improvement or
no change in mNIS+7 at 24 months, with a maximal 34.6-point
decrease. In a new post-hoc analysis exploring the relationship
between baseline neuropathy severity and change in mNIS+7, the
potential effect of patisiran was observed across the full range of
disease severity, including patients with a high degree of
neurologic impairment at baseline (N=9 with baseline NIS of 46-93
points). Specifically, in this group, patisiran administration was
associated with a mean 7.4-point decrease in mNIS+7. These results
demonstrate that patisiran has the potential to halt or improve
neuropathy progression across a broad range of neurologic
impairment.
Over the 24-month period, patients with evidence of cardiac
amyloid involvement at study entry (N=11) showed stability in their
cardiac biomarkers, echocardiographic measures, and 10-meter walk
test (gait speed). Additional results for patisiran in these hATTR
amyloidosis patients with cardiac involvement will be presented at
the European Society of Cardiology Heart Failure (ESC-HF) Congress,
being held April 29 – May 2, 2017 in Paris, France, on Saturday,
April 29th at 5:06 am ET. The data presentation will be posted on
Capella at that time.
Serum TTR levels were also measured throughout the Phase 2 OLE
study and showed patisiran-mediated TTR knockdown of up to 97
percent, with mean maximal knockdown of 93 percent and a mean
knockdown of approximately 82 percent over 24 months.
In the first post-hoc exploratory analysis of its kind, the
change in dermal TTR amyloid content over 24 months was assessed
through blinded evaluation of tandem skin punch biopsies from the
distal thigh and distal leg. Patisiran administration was
associated with a median reduction of up to 78 percent in dermal
amyloid content over time as compared to baseline, with
statistically significant mean decreases in dermal amyloid content
at 24 months in both the distal thigh and distal leg (p less than
0.05). This decrease in mean dermal amyloid content is consistent
with the statistically significant mean increase in sweat gland
nerve fiber density observed from the same skin biopsy samples over
24 months. Taken together, these exploratory analyses support the
therapeutic hypothesis that reduction of mutant and wild-type TTR
can potentially lead to reduction of TTR amyloid deposition and
increased nerve regeneration.
Patisiran administration was found to be generally well
tolerated in patients with hATTR amyloidosis out to 25 months, with
no drug-related serious adverse events (SAEs) reported.
Drug-related or possibly drug-related adverse events (AEs) in four
or more patients were flushing (22.2%) and infusion-related
reactions (22.2%), all of which were mild in severity and did not
result in any discontinuations. There were ten reports of serious
adverse events (SAEs) in seven patients, all of which were
unrelated to study drug, including two previously reported deaths.
There were no clinically significant changes in liver function
tests, renal function, or hematologic parameters, including
platelets. Following treatment in the Phase 2 OLE study, all 25
eligible patients enrolled in the APOLLO-OLE study; 20 have
received at least 36 months of dosing as of April 12, 2017.
To view all the results presented by Alnylam at the AAN and
ESC-HF meetings, please visit www.alnylam.com/capella.
About the Patisiran Phase 2 OLE Study
The patisiran Phase 2 OLE study was an open-label, multi-center
trial designed to evaluate the long-term safety and tolerability of
patisiran administration in patients with polyneuropathy due to
hereditary ATTR (hATTR) amyloidosis that were previously enrolled
in a Phase 2 study. Patisiran was administered once every 3 weeks
at a dose of 0.3 mg/kg by intravenous infusion. The study measured
a number of clinical endpoints every six months, including mNIS+7,
which is an evaluation of muscle weakness, sensory and autonomic
function, and nerve conductance, where neuropathy progression leads
to an increased score over time. The change in the mNIS+7
measurement from baseline to 18 months is the primary endpoint in
the Company's APOLLO Phase 3 trial of patisiran in patients with
hATTR amyloidosis. Patients who completed the Phase 2 OLE study
were eligible to screen for the global APOLLO-OLE study, in which
they have the opportunity to receive patisiran on an ongoing
basis.
About the APOLLO Phase 3 Study
The APOLLO Phase 3 trial is a randomized, double-blind,
placebo-controlled, global study designed to evaluate the efficacy
and safety of patisiran in hATTR amyloidosis patients with
polyneuropathy. The primary endpoint of the study is the difference
in the change in mNIS+7 between patisiran and placebo at 18 months.
Secondary endpoints include: the Norfolk Quality of Life-Diabetic
Neuropathy (QOL-DN) score; NIS-weakness; modified BMI; timed
10-meter walk; and the COMPASS-31 autonomic symptom score. The
trial enrolled 225 hATTR amyloidosis patients that were randomized
2:1, patisiran:placebo, with patisiran administered at 0.3 mg/kg
once every three weeks for 18 months. The study was designed with
90 percent power to conservatively detect as little as a 37.5
percent difference in change in mNIS+7 between treatment groups,
with a two-sided alpha of 0.05. The placebo mNIS+7 progression rate
was derived from an Alnylam analysis of natural history data from
283 hATTR amyloidosis patients. All patients completing the APOLLO
Phase 3 study are eligible to screen for the global APOLLO-OLE
study, in which they have the opportunity to receive patisiran on
an ongoing basis.
Sanofi Genzyme Alliance
In January 2014, Alnylam and Sanofi Genzyme, the specialty care
global business unit of Sanofi, formed an alliance to accelerate
and expand the development and commercialization of RNAi
therapeutics across the world. The alliance is structured as a
multi-product geographic alliance in the field of rare diseases.
Alnylam retains product rights in the United States, Canada and
Western Europe, while Sanofi Genzyme obtained the right to access
certain programs in Alnylam's current and future Genetic Medicines
pipeline in the rest of the world (ROW) through the end of 2019,
together with certain broader co-development/co-commercialization
rights and global rights for certain products. In the case of
patisiran, Alnylam will advance the product in the United States,
Canada and Western Europe, while Sanofi Genzyme will advance the
product in the ROW.
About hATTR Amyloidosis
Hereditary transthyretin (TTR)-mediated amyloidosis (hATTR) is
an inherited, progressively debilitating, and often fatal disease
caused by mutations in the TTR gene. TTR protein is produced
primarily in the liver and is normally a carrier of vitamin A.
Mutations in TTR cause abnormal amyloid proteins to accumulate and
damage body organs and tissue, such as the peripheral nerves and
heart, resulting in intractable peripheral sensory neuropathy,
autonomic neuropathy, and/or cardiomyopathy. hATTR amyloidosis
represents a major unmet medical need with significant morbidity
and mortality, affecting approximately 50,000 people worldwide.
hATTR amyloidosis patients have a life expectancy of 2.5 to 15
years from symptom onset, and the only approved treatment options
for early stage disease are liver transplantation and tafamidis
(approved in Europe, Japan, and certain countries
in Latin America). There is a significant need for novel
therapeutics to treat patients with hATTR amyloidosis.
About LNP Technology
Alnylam has licenses to Arbutus Biopharma LNP intellectual
property for use in RNAi therapeutic products using LNP
technology.
About RNAi
RNAi (RNA interference) is a revolution in biology, representing
a breakthrough in understanding how genes are turned on and off in
cells, and a completely new approach to drug discovery and
development. Its discovery has been heralded as "a major scientific
breakthrough that happens once every decade or so," and represents
one of the most promising and rapidly advancing frontiers in
biology and drug discovery today which was awarded the 2006 Nobel
Prize for Physiology or Medicine. RNAi is a natural process of gene
silencing that occurs in organisms ranging from plants to mammals.
By harnessing the natural biological process of RNAi occurring in
our cells, the creation of a major new class of medicines, known as
RNAi therapeutics, is on the horizon. Small interfering RNA
(siRNA), the molecules that mediate RNAi and comprise Alnylam's
RNAi therapeutic platform, target the cause of diseases by potently
silencing specific mRNAs, thereby preventing disease-causing
proteins from being made. RNAi therapeutics have the potential to
treat disease and help patients in a fundamentally new way.
About Alnylam Pharmaceuticals
Alnylam (Nasdaq: ALNY) is leading the translation of RNA
interference (RNAi) into a whole new class of innovative medicines
with the potential to transform the lives of patients who have
limited or inadequate treatment options. Based on Nobel
Prize-winning science, RNAi therapeutics represent a powerful,
clinically validated approach for the treatment of a wide range of
debilitating diseases. Founded in 2002, Alnylam is delivering on a
bold vision to turn scientific possibility into reality, with a
robust discovery platform and deep pipeline of investigational
medicines, including three product candidates that are in
late-stage development or will be in 2017. Looking forward, Alnylam
will continue to execute on its “Alnylam 2020” strategy of building
a multi-product, commercial-stage biopharmaceutical company with a
sustainable pipeline of RNAi-based medicines. For more information
about our people, science and pipeline, please visit
www.alnylam.com and engage with us on Twitter at @Alnylam.
Alnylam Forward Looking Statements
Various statements in this release concerning Alnylam's future
expectations, plans and prospects, including, without limitation,
Alnylam's views with respect to the potential for RNAi
therapeutics, including the continued development of patisiran in
the ongoing APOLLO Phase 3 study and APOLLO-OLE study, its
expectations regarding the expected timing for reporting top-line
data from the APOLLO study of patisiran, and its expectations
regarding the safety and tolerability of its products in clinical
development, including patisiran, constitute forward-looking
statements for the purposes of the safe harbor provisions under The
Private Securities Litigation Reform Act of 1995. Actual results
and future plans may differ materially from those indicated by
these forward-looking statements as a result of various important
risks, uncertainties and other factors, including, without
limitation, Alnylam's ability to discover and develop novel drug
candidates and delivery approaches, successfully demonstrate the
efficacy and safety of its product candidates, the pre-clinical and
clinical results for its product candidates, which may not be
replicated or continue to occur in other subjects or in additional
studies or otherwise support further development of product
candidates for a specified indication or at all, actions or advice
of regulatory agencies, including actions by regulators concerning
product candidates, which may affect the initiation, timing and
progress of clinical trials, obtaining, maintaining and protecting
intellectual property, Alnylam's ability to enforce its
intellectual property rights against third parties and defend its
patent portfolio against challenges from third parties, obtaining
and maintaining regulatory approval, pricing and reimbursement for
products, progress in establishing a commercial and ex-United
States infrastructure, competition from others using technology
similar to Alnylam's and others developing products for similar
uses, Alnylam's ability to manage its growth and operating
expenses, obtain additional funding to support its business
activities, and establish and maintain strategic business alliances
and new business initiatives, Alnylam's dependence on third parties
for development, manufacture and distribution of products, the
outcome of litigation, the risk of government investigations, and
unexpected expenditures, as well as those risks more fully
discussed in the "Risk Factors" filed with Alnylam's most recent
Annual Report on Form 10-K filed with the Securities and
Exchange Commission (SEC) and in other filings that Alnylam
makes with the SEC. In addition, any forward-looking
statements represent Alnylam's views only as of today and should
not be relied upon as representing its views as of any subsequent
date. Alnylam explicitly disclaims any obligation, except to the
extent required by law, to update any forward-looking
statements.
The scientific information discussed in this news release
relating to Alnylam’s investigational therapeutic patisiran is
preliminary and investigative. Patisiran has not been approved by
the U.S. Food and Drug Administration, European Medicines Agency,
or any other regulatory authority and no conclusions can or should
be drawn regarding its safety or effectiveness.
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version on businesswire.com: http://www.businesswire.com/news/home/20170426005195/en/
Alnylam Pharmaceuticals, Inc.Christine Regan Lindenboom,
617-682-4340(Investors and Media)orJosh Brodsky,
617-551-8276(Investors)
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